The goal of this clinical research study is to find the highest
tolerable dose of the combinations of AG-120 and azacitidine and AG-221
and azacitidine that can be given to patients with AML. Researchers
also want to learn more about the effects of the drugs in combination
with azacitidine compared to azacitidine alone.

Phase 1b (Dose-Escalation Stage) Primary Objectives To assess the
safety and tolerability of the combination treatments of oral AG-120
plus subcutaneous (SC) azacitidine and oral AG-221 plus SC azacitidine
in subjects with newly diagnosed AML harboring an IDH1 or an IDH2
mutation, respectively, who are not candidates to receive
intensive inductive chemotherapy (IC). To establish the recommended
Phase 2 dose (RP2D) of oral AG-120 and oral AG-221 when
administered with SC azacitidine. Secondary Objective To assess the
preliminary efficacy of the combination treatments of oral AG-120 plus
SC azacitidine and oral AG-221 plus SC azacitidine in subjects with
newly diagnosed AML harboring an IDH1 or an IDH2 mutation,
respectively, who are not candidates to receive intensive IC.
Exploratory Objective - Phase 1 (Dose Escalation) To evaluate the PD of
oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when
administered in combination in this population. Phase 2 (Randomized
Stage) Primary Objective To assess the efficacy of the combination
treatments of oral AG-120 plus SC azacitidine and oral AG-221 + SC
azacitidine versus SC azacitidine in subjects with newly diagnosed
AML harboring an IDH1 or an IDH2 mutation, respectively, who are
not candidates to receive intensive IC. Secondary Objective To
evaluate the safety of oral AG-120 and oral AG-221 when administered
with SC azacitidine. To characterize the pharmacokinetics (PK) of
oral AG-120, AG-221, when administered in combination with SC
azacitidine. To evaluate the effect of oral AG-120 and oral AG-221 when
administered with SC azacitidine versus SC azacitidine alone on
health-related quality-of-life (HRQoL) outcomes. Exploratory
Objective - Phase 2 (Randomized) To evaluate pharmacodynamic effects of
oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when
administered in combination as well as azacitidine as a single agent in
this population. To evaluate molecular and cellular markers which
may be predictive of antitumor activity and/or resistance. Other
correlative analysis may include the evaluation of minimal residual
disease (MRD), to assess IDH1 and IDH2 variant allele fraction
(VAF) in blood and bone marrow cells. To assess changes in cellular
differentiation and changes in histone and deoxyribonucleic acid (DNA)
methylation profiles of IDH1 and IDH2 mutated leukemic cells as well as
wild-type IDH leukemic cells induced by oral AG-120 and oral
AG-221 when administered with SC azacitidine. To evaluate the effect of
oral AG-120 and oral AG-221 when administered with SC azacitidine versus
SC azacitidine alone on healthcare resource utilization.

1) Subject is >/= 18 years of age at the time of signing the informed
consent form (ICF).
2) Subject must understand and voluntarily sign an ICF prior to any
study-related assessments/procedures being conducted.
3) Subject is willing and able to adhere to the study visit schedule and
other protocol requirements.
4) Subject has previously untreated primary (ie, de novo) or secondary
(progression of MDS or myeloproliferative neoplasms [MPN], or
therapy-related) AML according to the WHO classification with >/= 20%
leukemic blasts in the bone marrow: a. Have an IDH1 or IDH2 gene
mutation (R132, R140, or R172) - IDH mutational status will be assessed
locally; for sites without local testing capabilities, a referral lab
will identified. By the investigator’s assessment who are not candidates
to receive intensive IC.
5) Subject has an Eastern Cooperative Oncology Group (ECOG) performance
status of 0, 1 or 2.
6) Subject has adequate organ function defined as: Serum aspartate
aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and
alanine aminotransferase (ALT/SGPT) < 3 x ULN, unless considered due
to leukemic organ involvement. Serum total bilirubin < 1.5 x ULN.
Higher levels are acceptable if these can be attributed to ineffective
erythropoiesis, 3 times the upper limit of normal for Gilbert’s syndrome
(eg, a gene mutation in UGT1A1), or leukemic organ involvement. Serum
creatinine < 2 x ULN or creatinine clearance >30 mL/min based on
the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 -
Age) x (weight in kg) x (0.85 if female) / 72 x serum creatinine
7) Agree to serial bone marrow aspirate/biopsies.
8) Females of childbearing potential (FCBP) may participate, providing
they meet the following conditions: Agree to abstain from sexual
intercourse or to use at least two highly effective contraceptive
methods (eg, combined [containing estrogen and progestogen] or
progestogen alone associated with inhibition of ovulation, oral,
injectable, patch, or implantable hormonal contraceptive; bilateral
tubal occlusion; intra-uterine device; intrauterine hormone-releasing
system; or male partner sterilization) at screening and throughout the
study, and for 4 months following the last study treatment; and
9) (continuation of inclusion #8) -and Have a negative serum b-subunit
of human chorionic gonadotropin (b-hCG) pregnancy test (sensitivity of
at least 25 mIU/mL) at screening; and Have a negative serum b-hCG
pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior
to the start of study treatment in the Treatment Period (note that the
screening serum pregnancy test can be used as the test prior to the
start of study treatment in the Treatment Period if it is performed
within the 72-hour timeframe).
10) Male subjects (with a female partner of childbearing potential who
must agree to conditions in criterion 8) abstain from sexual intercourse
or to the use of at highly effective contraceptive methods at screening
and throughout the course of the study and should avoid fathering a
child during the course of the study and for 4 months following the last
study treatment (6 months following the last dose of azacitidine in Canada).

Exclusion:

1) Subject is suspected or proven to have acute promyelocytic leukemia
based on morphology, immunophenotype, molecular assay, or karyotype.
2) Subject has AML secondary to chronic myelogenous leukemia
3) Subject has received a targeted agent against an IDH1 or IDH2 mutation.
4) Subject has received prior systemic anticancer therapy, HSCT, or
radiotherapy for AML. Note that hydroxyurea is allowed prior to the
start of study treatment for the control of leukocytosis in subjects
with white blood cell (WBC) counts >/= 30 x 109/L (however,
hydroxyurea should not be given within 72 hours prior to and after
administration of azacitidine). For subjects with secondary AML (eg, MDS
or MPN) treatment for prior cancer is not exclusionary; full treatment
information will be collected within the CRF.
5) Subject has received prior treatment with azacitidine or decitabine
for MDS.
6) Subject has or is suspected of having central nervous system (CNS)
leukemia. Evaluation of cerebrospinal fluid is only required if CNS
involvement by leukemia is suspected during screening.
7) Subject has immediate life-threatening, severe complications of
leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock,
and/or disseminated intravascular coagulation.
8) Subject has significant active cardiac disease within 6 months prior
to the start of study treatment, including New York Heart Association
(NYHA) class III or IV congestive heart failure ; acute coronary
syndrome (ACS); and/or stroke; or left ventricular ejection fraction
(LVEF) </= 40% by echocardiogram (ECHO) or multi-gated acquisition
(MUGA) scan obtained within 28 days prior to the start of study treatment.
9) Subject has prior history of malignancy, other than MDS, MPN, or AML,
unless the subject has been free of the disease for >/= 1 year prior
to the start of study treatment. However, subjects with the following
history/concurrent conditions are allowed: Basal or squamous cell
carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ
of the breast Incidental histologic finding of prostate cancer (T1a or
T1b using the tumor, node, metastasis clinical staging system)
10) Subject is known seropositive for or has active viral infection with
human immunodeficiency virus (HIV), or active infection with hepatitis B
virus (HBV) or hepatitis C virus (HCV)
11) Subject is known to have dysphagia, short-gut syndrome,
gastroparesis, or other conditions that limit the ingestion or
gastrointestinal absorption of drugs administered orally
12) Subject has uncontrolled hypertension (systolic blood pressure [BP]
>/= 180 mmHg or diastolic BP >/= 100 mmHg)
13) Subject is taking the following sensitive CYP substrate medications
that have a narrow therapeutic range are excluded from the study unless
the subject can be transferred to other medications at least 5
half-lives prior to the start of study treatment: phenytoin (CYP2C9),
S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2).
14) Subject is taking the breast cancer resistance protein (BCRP)
transporter-sensitive substrate rosuvastatin; subject should be excluded
from the study unless he/she can be transferred to other medications at
least 5 half-lives prior to the start of study treatment
15) Subject has active uncontrolled systemic fungal, bacterial, or viral
infection (defined as ongoing signs/symptoms related to the infection
without improvement despite appropriate antibiotics, antiviral therapy,
and/or other treatment).
16) Subject has known or suspected hypersensitivity to any of the
components of study therapy.
17) Subject is taking medications that are known to prolong the QT
interval unless he/she can be transferred to other medications within
>/= 5 half-lives prior to the start of study treatment. (If
equivalent medication is not available, QTc will be closely monitored.)
18) Subject has QTc interval (ie, Fridericia’s correction [QTcF]) >/=
450 ms or other factors that increase the risk of QT prolongation or
arrhythmic events (eg, heart failure, hypokalemia, family history of
long QT interval syndrome) at screening.
19) Female subject who is pregnant or lactating.
20) Subject has any significant medical condition, laboratory
abnormality, or psychiatric illness that would prevent the subject from
participating in the study.
21) Subject has any condition, including the presence of laboratory
abnormalities, that places the subject at unacceptable risk if he/she
were to participate in the study.
22) Subject has any condition that confounds the ability to interpret
data from the study.